tbuckley/cabot-search huggingface dataset:
Preservation of liver function with local radiation therapy in patients with metastatic intrahepatic cholangiocarcinoma with extrahepatic disease.
Authors: Rituraj Upadhyay, Ethan B. Ludmir, Brian De, Emma Holliday, Grace L. Smith, Cullen M. Taniguchi, Prajnan Das, Bruce D. Minsky, Albert C. Koong, Milind M. Javle, Sunyoung S. Lee, Jean-Nicolas Vauthey, Ching-Wei D. Tzeng, Hop Tran Cao, Eugene Jon Koay
Journal: Journal of Clinical Oncology (2022)

4080 Background: Tumor related liver failure (TRLF) is the most common cause of death in patients with metastatic intrahepatic cholangiocarcinoma (mICC) accounting for up to 72% deaths in patients treated with systemic therapy alone. We present our institutional experience of treating mICC patients with local liver-directed radiation therapy (RT). Methods: ICC patients with extrahepatic metastatic disease who received radiation therapy at our center with a biologically equivalent dose (BED) of at least 50 Gy from January 1, 2011 to March 31, 2021 were included in our study. Patient, tumor and treatment characteristics as well as the survival outcomes were recorded. TRLF was considered the cause of death if the patient died due to liver failure; and freedom from TRLF (FFTRLF) at 1 year and 2 years after RT was calculated. Results: Sixty-seven patients were included in the study. The median age was 63 years (range 29-83 years) and median RT dose was 60 Gy (range, 40-100 Gy). 73.1% patients received a BED &gt; 80.5 Gy. All except 1 patient were treated with upfront induction chemotherapy, followed by RT to the primary lesion in liver with (71.6%) or without (28.4%) concurrent chemotherapy. The most common induction chemotherapy regimen used was gemcitabine and cisplatin (65.7%) followed by gemcitabine, cisplatin and paclitaxel (22.4%), while the most common concurrent systemic therapy was capecitabine. Out of 43 patients with satellitosis, 29 were treated with RT to the dominant liver lesion while 14 received RT to the primary as well as one or more satellites. Overall, 15 patients (22.4%) had local progression of the radiated lesion, 42 patients (62.7%) progressed elsewhere in liver, and 52 patients (77.6%) had a distant progression. TRLF was the cause of death in 28.4% of patients. Median OS from diagnosis was 25 months while median OS after RT was 11.9 months. The 1- and 2-year rates of FFTRLF were 73.1% and 58.2% respectively, which were significantly higher than 1- and 2-year OS after RT (47.1% and 24.7% respectively, p &lt; 0.005). Univariate analysis did not identify significant association of FFTRLF or OS with age, sex, performance status, size of liver lesions, T or N stage, satellitosis, vascular thrombosis, TRLF, timing of metastasis, site of metastasis, RT technique and dose and chemotherapy. Conclusions: Liver directed radiation therapy in patients with mICC with extrahepatic disease appears to have favorable rates of TRLF and survival times, compared to historical data. Future prospective studies are warranted to define the survival benefit in these patients attributable to radiation therapy.
A novel molecular subtype of hepatocellular carcinoma based on the tumor purity and tumor microenvironment-related polygenic risk scores.
Authors: Yan Lin, Rong Liang, Xing Gao, Ziqin He, Lu Lu, Min Luo, Qian Li, Xiaobo Wang, Yongqiang Li, Guobin Wu, Xiaoling Luo, Jiazhou Ye
Journal: Journal of Clinical Oncology (2022)

e15040 Background: The molecular classification of hepatocellular carcinoma (HCC) plays a vital role in the management of precision therapy. Several molecular classification systems, mainly focusing on the tumor cells, were developed according to distinct omics features of HCC. Heterogeneous tumor microenvironment (TME) in HCC is recognized as a crucial part of inter-tumor heterogeneity. Few molecular classifications of HCC have so far taken into account both the related molecules of tumor cells and TME. Methods: Wefirstly identified the tumor purity (TP)-related and TME-related genes in the differentially expressed genes in HCC using GSE14520 data set, and separately constructed the TP-related and TME-related polygenic risk score (PRS). Secondly, according to the TP-related and TME-related PRSs, we proposed the TP-TME risk classification which was validated in two external data sets from The Cancer Genome Atlas Program and International Cancer Genome Consortium database. We also performed functional enrichment and drug repositioning analysis to reveal the potential biological heterogeneity among different subtypes. Results: The three TP-TME risk subtypes of HCC had significantly different prognosis and biological characteristics. The TP-TME low risk subtype had the best prognosis and was characterized by well-differentiated, the TP-TME high risk subtype had the worst prognosis and was characterized by aberrant activation of TGFβ and WNT pathways, and the TP-TME high risk subtype had the moderate prognosis and was characterized by exhibited activated MYC targets and proliferation-related gene sets. We also found that these three TP-TME risk subtypes may respond differently to immunotherapy (e.g., immune checkpoint inhibitors and chimeric antigen receptor-modified T cells) or other drug therapies. Conclusions: By combining separately constructed TP-related PRS and TME-related PRS, we proposed and validated a novel molecular classification system, the TP-TME risk subtyping system, to divide patients with HCC into three subtypes with distinct biological characteristics and prognosis. These findings highlight the significant clinical implications of the TP-TME risk subtyping system and provide potential personalized immunotherapy strategies for patients with HCC.
Clinical characteristics, treatment and clinical outcomes of leiomyosarcoma: A retrospective study from single center.
Authors: Yang Liu, Xiao-Wen Wang, Hong-Chen Ji, Jing-Yue Yang, Yan Chen, Zhen Wang, Hong-Mei Zhang
Journal: Journal of Clinical Oncology (2022)

e23536 Background: Leiomyosarcomas are genetically heterogeneous tumors with highly variable survival. The clinical efficacy of different treatments has not been determined. This retrospective study analyzed the clinical pathological features, treatments and outcomes of leiomyosarcoma patients. Methods: A retrospective review was performed of leiomyosarcoma patients between 2000 to 2021. 214 patients were initially investigated, 102 patients were excluded owing to a lack of follow-up or loss of data., and 112 patients were finally analyzed. Treatment outcomes were measured using overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). Optimal responses of first-line chemotherapies were also investigated under RECIST criteria. Results: Mean age of patients was 52.63 years, and male to female ratio was 1/2.2. Tumors mainly located in head and neck (2.68%), trunk and extremities (35.71%), abdomen and thoracic organs (16.07%), retroperitoneum (17.86%) and pelvis (27.68%). Patients with ⅠA, ⅠB, II, IIIA, IIIB and IV stage was 15.18%, 23.21%, 9.82%, 12.50%, 7.14% and 9.82% respectively. 2 patients received only chemotherapy after diagnosis, and 109 patients underwent surgery, among them 33.04% (37 cases) of patients had further radiation or chemotherapy. The median OS (mOS) of all patients was 42.65 months (95% CI 33.77-50.43). Adjuvant therapy had no significant influence on median DFS (mDFS) (28.63 months vs 30.33 months, P= 0.888). Significantly, R0 resection prolonged mDFS (33.30 months vs 7.37 months, P = 0.019) and mOS (102.5 months vs 35.83 months, P= 0.001). 32 patients occurred recurrence and all had surgery. 28 patients occurred metastases and 6 of them received surgery alone, 11 patients had systemic treatment, 6 patients received both treatments, 5 of them were untreated. In patients with metastases, the median PFS of systemic treatment (15.33 months) was shorter than median DFS of local treatment (48.83 months), while systemic treatment achieved similar survival time as surgery (78.03 months vs 79.27 months, P= 0.651). The disease control rate (DCR) of anthracycline-based regimens, ifosfamide (IFO), gemcitabine-based regimens and targeted therapy was 52.94%, 33.33%, 33.33%, 50% respectively. Conclusions: Surgery with R0 margin improved survival significantly of leiomyosarcoma patients. For survival time of patients with metastases, systemic treatment was not inferior to surgery, and anthracycline-based regimens had a higher disease control rate.
Pan-cancer (ca) analysis of the safety and efficacy of immune checkpoint inhibitors (ICI) in patients (pts) living with HIV (PLWH): Results from the international CATCH-IT consortium.
Authors: Talal El Zarif, Amin Nassar, Elio Adib, Jiaming Huang, Rana R. McKay, Ryan Dobbs, Nazli Dizman, Claire Drolen, Elie Kozaily, Anwaar Saeed, Caroline Nebhan, Michael Lorentsen, Javier Baena, Alessia Dalla Pria, Lindsey Baden, Ramya Ramaswami, Toni K. Choueiri, Kathryn Anne Lurain, Guru P. Sonpavde, Abdul Rafeh Naqash
Journal: Journal of Clinical Oncology (2022)

2649 Background: PLWH and ca are inadequately represented in clinical trials evaluating ICI especially in the setting of low CD4 counts (ct) and elevated HIV viral loads (VL). We assembled an international cohort of PLWH and ca treated with ICI to evaluate toxicity profiles and clinical outcomes. Methods: We retrospectively collected data on 204 PLWH and ca receiving ≥ 1 cycle of ICI between 2015-2021 at 14 academic medical centers in the US and Europe. Immune-related adverse events (irAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) V5.0. Baseline CD4 ct, CD8 ct and HIV VL were collected within 3 months (mo) of ICI initiation when available. Fisher’s exact test was performed to compare categorical variables. Median (med) Overall Survival (OS) and Objective Response Rate (ORR) were calculated for 186 pts treated in the metastatic (met) setting. Results: Among 204 PLWH treated with ICI, 174 (85%) were cis-gender males. 61 (31%) were Black and 34 (18%) were Hispanic/Latinx. Pts were treated with pembrolizumab (n=93), nivolumab (n=71), atezolizumab (n= 20), nivolumab and ipilimumab (n=13), durvalumab (n=6), or avelumab (n=1). Med number of prior lines of systemic therapy was 1 (range: 0-5). Among pts with available baseline data, 36/133 (27%) had CD4 ct &lt;200 cells/µL while 12/136 (9%) had VL ≥400 copies/mL. irAEs of any grade occurred in 43 (21%) pts and 13 (7%) were grade ≥3 while 19 (9%) required steroids. Pts with CD4 ct &lt;200 cells/µL experienced fewer irAEs than pts with CD4 ct ≥200 cells/µL (2/36 vs 26/97; p&lt;0.01). The incidence of any grade irAEs was similar between pts with CD4/CD8 ratio &lt;0.4 vs ≥0.4 (8/54 vs 18/72; p=0.16) and between pts with HIV VL ≥400 vs &lt;400 copies/mL (1/12 vs 28/124; p=0.46). Clinical outcomes are shown in the table below. Among 29 pts with met non-small cell lung ca (NSCLC) with available CD4 ct, the ORR of pts with CD4 ct &lt;200 cells/µL was 13% (95% CI:0-53) vs 38% (95% CI:18-62) in pts with CD4 ct ≥ 200 cells/µL (1/8 vs 8/21; p=0.38). Conclusions: In the largest dataset to our knowledge, we demonstrate tolerability and activity of ICI among PLWH regardless of CD4 ct and HIV VL levels. CD4 ct &lt;200 cells/µL may be associated with a lower incidence of irAEs. An analysis of a larger cohort is underway. [Table: see text]
Immune checkpoint inhibitor-related endocrinopathies: A nationwide population-based study.
Authors: Dina Elantably, Abdul Rahman Al Armashi, Faris Hammad, Akram Alkrekshi
Journal: Journal of Clinical Oncology (2022)

2653 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, unleashing the body’s immune system against cancer is not without consequences and may trigger immune-related adverse events (irAEs), such as endocrinopathies. Real-world data of these endocrinopathies is lacking. This study aims to obtain the prevalence of endocrine irAEs and identify possible underlying demographic risk factors or disparities. Methods: A cross-sectional study was performed using a US-based population database (Explorys) that aggregates records from 26 healthcare systems and includes over 79 million patients. Our sample included all patients on an ICI, and we further identified patients who developed endocrinopathies while on different ICI regimens. The demographic data extracted was categorical, hence presented as counts and percentages. The odds ratio (OR), standard error, and 95% confidence interval were calculated with the use of SPSS software version 28.0 (IBM). Results: There were 20,950 patients on an ICI; 58% males, 83% Caucasians, 10% African-Americans (AA), 38% aged between 18-65, and 63% were over 65 years. The prevalence of the studied endocrinopathies is listed in the table. The most prevalent ICI-induced endocrinopathy was hypothyroidism (7.9-13%). Combination therapy with ipilimumab and nivolumab showed the highest prevalence of ICI-induced endocrinopathies, followed by durvalumab. The odds of developing ICI-induced endocrinopathy were significantly higher with combination therapy than nivolumab monotherapy (OR 1.6; 95% CI 1.4-1.9). There was no statistically significant difference in endocrinopathy prevalence when comparing Caucasians to AA and adults18-65 years to seniors over 65 years. Conclusions: This is the largest epidemiological study of ICI-related endocrinopathies. We find an intriguing divergence from endocrinopathy prevalence reported in the literature and real-world data we are presenting here. Over diagnosis of overt hypothyroidism, as opposed to subclinical hypothyroidism, is concerning as the former necessitates levothyroxine therapy. More alarming is the under diagnosis of hypopituitarism and PAI, in which delay in treatment can be fatal. The diagnosis of these conditions can be challenging. Raising awareness, setting protocols for testing, and involving endocrinologists are crucial. Further studies are needed to clarify our findings. [Table: see text]
BRAF-targeted therapy for locally advanced ameloblastoma of the mandible: A potential neoadjuvant strategy.
Authors: Shirly Grynberg, Yael Steinberg, Nethanel Asher, Guy Ben-betzalel, Ronen Stoff, Gal Markel, Ronnie Shapira-Frommer, Jacob Schachter, Ariel Hirschhorn
Journal: Journal of Clinical Oncology (2022)

3149 Background: Ameloblastoma is a rare benign but locally aggressive odontogenic neoplasm, with 2% of cases representing ameloblastic carcinoma or metastatic ameloblastoma. It affects young adults with high recurrence rates after surgery. The standard therapy is radical bone resection with subsequent functional, aesthetic &amp; psychological impairments. Therefore, other therapeutic options, including neoadjuvant approach, should be considered. Sixty to 70% of mandible Ameloblastoma carry a BRAF mutation, usually V600E, and previous case reports have shown durable responses to treatment with BRAF inhibitors in these patients. We sought to explore the possibility of neoadjuvant BRAF or BRAF+MEK inhibition as neoadjuvant treatment in mandible Ameloblastoma. Here we present results of 12 patients with locally advanced disease who were treated with BRAF with or without MEK inhibitors. Methods: Patients who were unable to undergo jaw preservation surgery for locally advanced Ameloblastoma with a BRAF V600E mutation were treated with Dabrafenib or Dabrafenib-Tratmetinib in an EAP form. Patient records were analyzed for baseline parameters, treatment regimen, toxicity, response to therapy and the ability to convert to a mandible preservation surgery. Data were collected and analyzed in accordance with Sheba Medical Center IRB approval. Statistical analyses were done with STATA v.17. Results: Twelve patients were treated with Dabrafenib/ Dabrafenib-Tratmetinib between 2017-2021. Five patients received BRAF-MEK inhibitors and 7 BRAF inhibitor alone. Median age was 21. Ten patients(83%) showed excellent response to therapy and have successfully converted from planned radical bone resection to mandible preservation surgery. The other 2 patients are still on therapy and have also showed deep responses that enable conversion to mandible preservation. Median time to surgery was 10 months. With median follow up of 18 months, no cases of recurrence were documented. Rate of adverse events was as expected with only 1 case of G3-4 (hepatitis). Conclusions: Targeted therapy with BRAF with or without MEK inhibition may serve as an important therapeutic tool for locally advanced Ameloblastoma with the potential of organ preservation treatment, and is an important example of oncological therapy assisting in non-cancerous tumors.
Advancing digital health innovation in oncology to improve the lives of cancer patients.
Authors: Smit Patel, Isabel Van De Keere, Jennifer Goldsack, Dana Elise Rollison, Edmondo Robinson
Journal: Journal of Clinical Oncology (2022)

e13609 Background: Oncology is renowned for leading innovation in research and in care. However, digital innovation in cancer care and research appears to be limited relative to other therapeutic areas. Methods: A multi-stakeholder roundtable, co-hosted by the Digital Medicine Society (DiMe) and Moffitt Cancer Center, convened experts from 35 leading organizations in life science R&amp;D, regulators, payers, innovators, and with core representation from cancer patients and patient experts. Discussions addressed the current state of digital innovation in cancer care, root causes of digital health innovation challenges in oncology, and identifying action-oriented approaches to collaborative solutions needed to advance the safe, effective, ethical, and equitable use of digital innovations in oncology. Results: There was consensus among roundtable attendees that digital innovation lags behind in oncology relative to other therapeutic areas. Challenges identified as ‘low hanging fruit’ for digital innovation include reducing patient administrative burden, supporting care navigation, optimizing decision making in care and research, optimizing clinical pathways, and improving how we monitor both performance status and safety. Reducing financial toxicity and disparities in disease burden must be imperatives of digital innovation in oncology. Access to care and health outcomes for all patients must also be improved. Impediments to digital innovation in oncology include a proliferation of digital point solutions as opposed to system level innovations; transactional digital solutions that do not promote ongoing engagement and reengagement for the lifetime of the patient journey; lack of trust among patients and clinicians; the absence of data sharing incentives and infrastructure; and business and payer disincentives to digital transformation. Conclusions: Digital innovation frameworks can support more effective and equitable approaches to care that are accessible, scalable, and inclusive, thereby reducing the burden of cancer. To achieve this, clinical, technical, and operational best practices necessary to develop, design, and deploy high-quality digital interventions into cancer care must be established. There is no reason for the successful adoption of digital interventions in oncology to lag behind other therapeutic areas. Intentional action with urgency is required by the multi-stakeholder community through a collaborative effort to realize the full promise of digital innovation for patients and the systems that support those who care for them.
Phase 1 study of C019199, an oral CSF-1R/DDRs/VEGFR2 multiple kinase inhibitor, to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors, including tenosynovial giant cell tumor.
Authors: Lin Shen, Feng Ye, Jifang Gong
Journal: Journal of Clinical Oncology (2022)

TPS3177 Background: C019199 was designed to be a tumor immune microenvironment (TME) modulator in order to improve the efficacy against tumor growth when combined with immune checkpoint inhibitors, like anti-PD1 or anti-PD-L1. It was shown to have a specific inhibition profile against CSF-1R, DDR1 and VEGFR2 with IC 50 of 14nM, 40nM and 79nM, respectively. CSF-1R’s inhibition may deplete Tumor-associated macrophages (TAMs) in TME, help the infiltration of T cells and enhance T cell responses. But a single modulating mechanism may not be strong enough or may be vulnerable and easily overcome by tumors. C019199 can reshape the TME by additionally inhibiting DDRs and VEGFR2, which may remove the "physical barrier" of tumor extracellular matrix and further increase T cell infiltration on top of inducing tumor blood vessels normalization. As a single agent with the appropriate combination of multiple modulation effects, it will potentially turn "cold" tumors into "hot" tumors. Preclinical studies have shown that C019199 inhibits tumor growth in multiple animal tumor models and has better antitumor efficacy when combined with immune checkpoint blockades. Methods: A first-in-human, open label, multicenter, dose-escalation/expansion study of C019199 is currently enrolling. Eligible subjects (age ≥ 18 years and &lt;76 years) with histologically or cytologically confirmed relapsed, refractory, or progressive metastatic solid tumors will be enrolled in. In Part A, the safety and tolerability of C019199 will be assessed in about 25 subjects to identify the maximum tolerated dose and recommended phase Ⅱ dose (PR2D). In Part B, the safety and antitumor activity of the RP2D will be assessed in about 60 subjects in disease-specific expansion cohorts. Primary endpoints are adverse events, laboratory abnormalities, dose-limiting toxicities. Secondary endpoints will include pharmacokinetics, objective response rate, progression-free survival, and disease control rate. Exploratory biomarker analyses include CSF-1 and VEGF. Clinical trial information: CTR20202045.